(Adapted from the application) Alzheimer's disease (AD) is defined by the presence in the brain of a fibrous protein aggregate known as amyloid plaque. Evidence from genetic, pathological, and biochemical studies suggests that amyloid fibril formation may cause neurodegeneration. Inhibition of amyloid formation is therefore a viable strategy for the design of potential AD therapeutic molecules; many industrial programs based on the idea are underway. In order to follow such a strategy, it is necessary to understand the structure of amyloid fibrils and the mechanism by which why form. However, the unusual physical properties of amyloid fibrils preclude their study by widely-applied biophysical methods. This project has as its goal to develop and apply new technology in order to produce a molecular model of AD amyloidogenesis. The model will be used to understand genetic risk factors for AD and to test potential amyloid inhibitors. It is hoped that this model will also allow testable predictions about the AD pathogenic pathway to be made. The group of scientists involved in the program project (the Boston Amyloid group) have a wide variety of backgrounds, ranging from physics to protein chemistry. The investigators, Peter Lansbury, and David Teplow have a history of accomplishment in the protein chemistry of neurodegenerative diseases and are colleagues in the Center for Neurologic Diseases at Bringham and Women's Hospital and Harvard Medical School. Their collaborators include individuals recognized for playing pivotal roles in the development of the three technologies which are the focus of proposal: Robert Griffin (solid state NMR), George Benedek (dynamic light scattering), and Charles Lieher (atomic force microscopy). The collaboration between groups which are focused on the elucidation of a medical problem is required in order to make progress in this difficult area. Another unique and important aspect of this program project is the inclusion of consultants from the pharmaceutical industry who are involved in exploiting amyloid as a therapeutic target. It is hoped that the advisory board will facilitate transfer of new technology to the private sector, where it can be used for the drug discovery process.